With the success of anti-estrogens as a major therapeutic modality in various stages of breast cancer, the role of anti-estrogens in chemoprevention has assumed a prominent role in the management of high-risk patients. However, anti-estrogen chemoprevention therapy is not without limitations and risks, thus, new chemoprevention agents that are more effective and less toxic are needed. In vivo studies have shown that 9-cis-retinoic acid (9cRA) or related retinoids that selectively interact with nuclear retinoid X receptors (RXRs) are effective in the prevention of mammary cancer either alone or in combination with anti-estrogens like tamoxifen or raloxifene. At UAB, we have designed and synthesized two new classes of RXR-selective tamoxifen or raloxifene. At UAB, we have designed and synthesized two new classes of RXR-selective- retinoids. We have already shown that one example, 9cuab30, is effective in vivo in a cancer chemopreventive mammary model and is non-toxic at this effective dose. We propose to further evaluate studies would: (a) determine the optimal dose of RXR-selective retinoids for mammary cancer prevention model; (b) determine if the combination of 9cUAB30 with other non-steroidal estrogen response modifiers, like tamoxifen, are additive or lead to synergistic prevention of mammary cancer, and (c) determine potential surrogate endpoint biomarkers. The demonstration that these retinoids are effective would lead to evaluating their toxicity (to determine a therapeutic index) and pharmacology. A diverse and effective team of scientists has been assembled with extensive expertise in retinoid research and clinical experience to move promising UAB retinoids to phase I clinical trials.